Statins and fenofibrate affect skeletal muscle chloride conductance in rats by differently impairing ClC-1 channel regulation and expression

Background and purpose:

Statins and fibrates can produce mild to life-threatening skeletal muscle damage. Resting chloride channel conductance (gCl), carried by the ClC-1 channel, is reduced in muscles of rats chronically treated with fluvastatin, atorvastatin or fenofibrate, along with increased resting cytosolic calcium in statin-treated rats. A high gCl, controlled by the Ca²⁺-dependent protein kinase C (PKC), maintains sarcolemma electrical stability and its reduction alters muscle function. Here, we investigated how statins and fenofibrate impaired gCl.

Experimental approach:

In rats treated with fluvastatin, atorvastatin or fenofibrate, we examined the involvement of PKC in gCl reduction by the two intracellular microelectrodes technique and ClC-1 mRNA level by quantitative real time-polymerase chain reaction. Direct drug effects were tested by patch clamp analysis on human ClC-1 channels expressed in human embryonic kidney (HEK) 293 cells.

Key results:

Chelerythrine, a PKC inhibitor, applied in vitro on muscle dissected from atorvastatin-treated rats fully restored gCl, suggesting the involvement of this enzyme in statin action. Chelerythrine partially restored gCl in muscles from fluvastatin-treated rats but not in those from fenofibrate-treated rats, implying additional mechanisms for gCl impairment. Accordingly, a decrease of ClC-1 channel mRNA was found in both fluvastatin-and fenofibrate-treated rat muscles. Fenofibric acid, the in vivo metabolite of fenofibrate, but not fluvastatin, rapidly reduced chloride currents in HEK 293 cells.

Conclusions and implications:

Our data suggest multiple mechanisms underlie the effect of statins and fenofibrate on ClC-1 channel conductance. While statins promote Ca²⁺-mediated PKC activation, fenofibrate directly inhibits ClC-1 channels and both fluvastatin and fenofibrate impair expression of mRNA for ClC-1.     

A word of caution: Early failure of Magmaris® bioresorbable stent after pulmonary artery stenting

Bioresorbable scaffolds (BRS) have been advocated as the fourth revolution in interventional cardiology medical devices with promising technology to improve the treatment of coronary artery disease with an event-free future. We describe the first reported use and early collapse of the Magmaris® Resorbable Magnesium Scaffold (RMS) stent (BIOTRONIK AG, Switzerland) to relieve left pulmonary artery severe stenosis in a newborn after the Norwood procedure. The stent collapse was detected 2 weeks after implantation and urgently treated with a balloon-expandable stent. This complication raises the alarm about the need to keep implanted RMS under scrutiny. The possibility of faster scaffold resorption in small babies or lack of sufficient radial force of RMS to resist acute vessel recoil has led to ineffective relief of branch pulmonary artery stenosis and failure to enable a safe short-term bridge to Stage II palliation.     

Color Error in the Digital Camera Image Capture Process

The color error in images taken by digital cameras is evaluated with respect to its sensitivity to the image capture conditions. A parametric study was conducted to investigate the dependence of image color error on camera technology, illumination spectra, and lighting uniformity. The measurement conditions were selected to simulate the variation that might be expected in typical telemedicine situations. Substantial color errors were observed, depending on the measurement conditions. Several image post-processing methods were also investigated for their effectiveness in reducing the color errors. The results of this study quantify the level of color error that may occur in the digital camera image capture process, and provide guidance for improving the color accuracy through appropriate changes in that process and in post-processing.     

Myxococcus CsgA,Drosophila Sniffer,and human HSD10 are cardiolipin phospholipases

Myxococcus xanthus development requires CsgA, a member of the short-chain alcohol dehydrogenase (SCAD) family of proteins. We show that CsgA and SocA, a protein that can replace CsgA function in vivo, oxidize the 2′-OH glycerol moiety on cardiolipin and phosphatidylglycerol to produce diacylglycerol (DAG), dihydroxyacetone, and orthophosphate. A lipid extract enriched in DAGs from wild-type cells initiates development and lipid body production in a csgA mutant to bypass the mutational block. This novel phospholipase C-like reaction is widespread. SCADs that prevent neurodegenerative disorders, such as Drosophila Sniffer and human HSD10, oxidize cardiolipin with similar kinetic parameters. HSD10 exhibits a strong preference for cardiolipin with oxidized fatty acids. This activity is inhibited in the presence of the amyloid β peptide. Three HSD10 variants associated with neurodegenerative disorders are inactive with cardiolipin. We suggest that HSD10 protects humans from reactive oxygen species by removing damaged cardiolipin before it induces apoptosis.     

The prognostic value of intraepithelial and stromal CD3‐, CD117‐ and CD138‐positive cells in non‐small cell lung carcinoma

Al‐Shibli K, Al‐Saad S, Andersen S, Donnem T, Bremnes RM, Busund L‐T. The prognostic value of intraepithelial and stromal CD3‐, CD117‐ and CD138‐positive cells in non‐small cell lung carcinoma. APMIS 2010; 118: 371–82. The major value of prognostic markers in potentially curable non‐small cell lung carcinoma (NSCLC) should be to guide therapy after surgical treatment. Although tumor‐infiltrating T lymphocytes and plasma cells have been documented in NSCLC, a clear association with clinical outcome, especially for the stromal component, has not been well established. The aim of this study was to elucidate the prognostic significance of these cells/markers in the epithelial and stromal compartments of NSCLC. Tissue microarrays from 335 resected, stage I‐IIIA, NSCLC were constructed by duplicate cores from viable neoplastic epithelial and stromal areas. Immunohistochemistry was used to evaluate the infiltration of CD3⁺, CD117⁺ as well as CD138⁺ cells in epithelial and stromal areas. In univariate analyses, increasing numbers of stromal CD3⁺ (p = 0.001) and epithelial CD3⁺ cells (p = 0.004) correlated significantly with an improved disease‐specific survival. No such relation was noted with CD3⁺ or CD117⁺ cells. In the multivariate analysis, stromal CD3⁺ cells was an independent prognostic factor for disease‐specific survival (HR 1.925, CI 1.21–3.04, p = 0.005). Increased presence of the pan T‐cell marker, CD3, which is an independent factor, correlates with improved clinical outcome in NSCLC. This prognostic impact of T cells is clearer in the tumor stroma. Neither plasma cells nor mast cells were prognostic indicators in our cohort.     

Musculotendinous architecture of pathological supraspinatus: A pilot in vivo ultrasonography study

Architectural changes associated with tendon tears of the supraspinatus muscle (SP) have not been thoroughly investigated in vivo with the muscle in relaxed and contracted states. The purpose of this study was to quantify the geometric properties within the distinct regions of SP in subjects with full‐thickness tendon tears using an ultrasound protocol previously developed in our laboratory, and to compare findings with age/gender matched normal controls. Twelve SP from eight participants (6 male/2 female), mean age 57 ± 6.0 years, were investigated. Muscle geometric properties of the anterior region (middle and deep parts) and posterior region (deep part) were measured using image analysis software. Along with whole muscle thickness, fiber bundle length (FBL) and pennation angle (PA) were computed for architecturally distinct regions and/or parts. Pathologic SP was categorized according to the extent of the tear in the tendon (with or without retraction). In the anterior region, mean FBL of the pathologic SP was similar with normal controls; however, mean PA was significantly smaller in pathologic SP with retraction compared with normal controls, in the contracted state (P < 0.05). Mean FBL in the posterior region in both relaxed and contracted states was significantly shorter in the pathologic SP with retraction compared with normal controls (P < 0.05). Findings suggest FBL changes associated with tendon pathology vary between the distinct regions, and PA changes are related to whether there is retraction of the tendon. The ultrasound protocol may provide important information on architectural changes that may assist in decision making and surgical planning. Clin. Anat., 2013. © 2012 Wiley Periodicals, Inc.     

A prospective study comparing the haemodynamic with the cross-sectional echocardiographic diagnosis of rheumatic tricuspid stenosis

The value of cross-sectional echocardiography in the diagnosisof tricuspid valve stenosis is not clearly established. We prospectivelystudied by cardiac catheterization 42 consecutive patients,with a mean age of 29 ± 11 years, who exhibited the cross-sectionalechocardiographic features of tricuspid valve stenosis, definedas: diastolic doming of all three tricuspid leaflets and leafletthickening with restrictive motion. To expose occult and amplifyborderline tricuspid diastolic gradients, simultaneous rightatrial and right ventricular pressures were recorded in thebasal state, after incremental infusions of normal saline to200,400,500, 700 or 1000 ml until a mean right atrial pressureof 12 mmHg was achieved, and finally after intravenous administrationof 0.6 mg of atropine. Eighteen patients, Group 1, (43%) exhibitedmean tricuspid diastolic gradients >2mmHg after saline infusion,increasing from a mean of4 ± 2 to 9 ± 3 mmHg,(P <0.001), 14 (33%) having gradients <2mmHg in the basalstate, together with four (10%) increasing from 1.7 ±0.2 to 4.5 ± l.2 mmHg (P <0.01) after provocationwith fluid challenge. In the remaining 24 patients, Group 2,(57%) the mean tricuspid diastolic gradient was <2 mmHg,both at rest and after provocative manoeuvres. We conclude thatthe cross-sectional echocardiographic features of tricuspidvalve stenosis are not a precise indicator of tricuspid valvestenosis. Provocative manoeuvres during haemodynamic studiesare required to expose occult or amplify borderline tricuspiddiastolic gradients in a minority of patients with the cross-sectionalechocardiographic features of tricuspid stenosis.